Abstract 286: ATPase Inhibitory Factor 1 Regulates Glycolysis in Cardiomyocytes

Abstract

It is known that pathological cardiac hypertrophy is associated with decreased fatty acid oxidation (FAO) and increased reliance on glycolysis. This metabolic remodeling is generally recognized and considered ultimately maladaptive for sustaining myocardial energetics and function. The mechanisms responsible for the switch are poorly understood but appear to be coupled with impaired mitochondrial function. We found that mitochondrial ATPase inhibitor factor 1 (ATPIF1) was up-regulated (by 4-fold, p=0.01) in the failing heart induced by TAC surgery as well as in hypertrophied adult rat cardiomyocytes (CMs) induced by 10 uM phenylephrine (PE, by 3-fold, p=0.01), but not in the physiological hypertrophied heart (p=0.9). ATPIF1 is an inhibitor of ATPase in the mitochondrial ATP synthase, or Complex V. It was shown that upregulation of ATPIF1 increased glycolysis in non-cardiomyocytes. Here we wish to test the hypothesis that ATPIF1 stimulates glycolysis in the heart undergoing pathological hypertrophy. Overexpress ATPIF1 (OE) by adenovirus vector in CMs, which mimics the up-regulation of ATPIF1 induced by PE, increased glycolysis in CMs (control: 8.54±0.61 mpH/min, OE: 11.46±0.48 mpH/min; p=0.006), while ATPIF1 knockdown (KD) by shRNA in PE treated CMs abolished the upregulation of glycolytic capacity (control: 29.27±1.31 mpH/min, KD: 28.61±1.81 mpH/min, control-PE: 40.12±1.33 mpH/min, KD-PE: 32.51±2.09 mpH/min; p=0.003). ATPIF1OE or pathological hypertrophy induced by PE increased the expression of glycolytic enzymes, e.g. GAPDH, GLUT1, LDHA and PKM2, which were abolished by ATPIF1KD. We also found that elevation of ATPIF1 decreased mitochondrial oxygen consumption rate (OCR) and promoted mitochondrial reactive oxygen species (mtROS) production, while the generation of mtROS caused by PE was abrogated in the ATPIF1 deficient CMs. Blockade of mtROS production by expressing mitochondria localized catalase suppressed the increased glycolysis in ATPIF1-OE CMs. In conclusion, our results identify ATPIF1 as a regulator of glycolysis in pathological cardiac hypertrophy, which may provide a mechanism for the regulation of glycolysis through mitochondrial bioenergetics.